In Utero Undernutrition in Male Mice Programs Liver Lipid Metabolism in the Second-Generation Offspring Involving Altered Lxra DNA Methylation
In Utero Undernutrition in Male Mice Programs Liver Lipid Metabolism in the Second-Generation Offspring Involving Altered Lxra DNA Methylation
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DOI：
10.1016/j.cmet.2014.03.026
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发表时间：
2014-06-03
期刊：
影响因子：
29
通讯作者：
Jimenez-Chillaron, Josep C.
中科院分区：
文献类型：
--
作者：
Martinez, Debora;Pentinat, Thais;Jimenez-Chillaron, Josep C.
肥胖和2型糖尿病有一个可遗传的组成部分，而不是归因于遗传因素。相反，表观遗传机制可能发挥作用。我们通过宫内营养不良建立了一种宫内生长受限（IUGR）小鼠模型。随着年龄的增长，IUGR小鼠出现肥胖和葡萄糖耐受不良。引人注目的是，IUGR雄性小鼠的后代也出现了葡萄糖耐受不良。在这里，我们表明，在子宫内营养不良的F1雄性影响F2小鼠肝脏中的脂肪生成基因的表达，部分原因是Lxra的表达改变。反过来，Lxra表达归因于其5' UTR区域的DNA甲基化改变。我们在它们的祖先F1雄性的精子中发现了相同的表观遗传特征。我们的数据表明，子宫内营养不良导致生殖细胞（F1）的表观遗传修饰，这些修饰随后在F2的体细胞中传播和维持，从而影响后代的健康和疾病风险。
Obesity and type 2 diabetes have a heritable component that is not attributable to genetic factors. Instead, epigenetic mechanisms may play a role. We have developed a mouse model of intrauterine growth restriction (IUGR) by in utero malnutrition. IUGR mice developed obesity and glucose intolerance with aging. Strikingly, offspring of IUGR male mice also developed glucose intolerance. Here, we show that in utero malnutrition of F1 males influenced the expression of lipogenic genes in livers of F2 mice, partly due to altered expression of Lxra. In turn, Lxra expression is attributed to altered DNA methylation of its 5' UTR region. We found the same epigenetic signature in the sperm of their progenitors, F1 males. Our data indicate that in utero malnutrition results in epigenetic modifications in germ cells (F1) that are subsequently transmitted and maintained in somatic cells of the F2, thereby influencing health and disease risk of the offspring.